Cycloadditions of azirines

The 3//-azepines obtained by cycloaddition of azirines to cyclopentadienones (see Section 3.1.1.1.2.) are thought to arise from the initially formed 2/7-azepines by [1,5]-H suprafacial sigmatropic shifts.31-108 In contrast, 1/Z-azepine 9 results from the thermal rearrangement of the nonisolable 2//-azepine-2-carboxylate 8.13 Presumably, the 1 //-azepine is stabilized, relative to the 3//-isomer, by intramolecular hydrogen bonding between the NH and the adjacent ester group. 

Cycloaddition of azirines 5 to 1.2,4,5-tetrazines 6 is followed by loss of nitrogen and ring enlargement to yield 5//-1,2,4-triazepines 7, which tautomerize spontaneously by a [1,51-hydrogen shift to the 2/7-1,2,4-triazepines 8. The triazepinesare accompanied by variable amounts of pyrimidines and pyrazoles.335 - 338... 

Cycloaddition of azirines can give fused systems as shown in Scheme 1 (72TL1353,74TL1487). 

An interesting Darzens-like formal cycloaddition of azirines has also been reported <2004EJ02421>. While this is not a true cycloaddition reaction, two bonds are formed in the same reaction sequence. Reaction of sulfone 114 with lithium diisopropylamide (LDA) generates a carbanion which then adds to the azirine to generate intermediate 115. Cyclization of this intermediate with the allyl halide provides the product aziridine 116. This reaction proceeds in only 13% yield but is nonetheless an interesting route to fused-ring aziridines (Equation 27). 

Cycloaddition of azirines. Irradiation of the azirinc 2 in the presence of DCN (1) forms a radical cation (3), which is trapped by imincs to form imidazoles (4). 

The photochemical cycloaddition of azirine 35 with cyclopentanone has been found to depend on the experimental conditions. When 35 is irradiated and cyclopentanone is slowly added, the expected s/ /ro-S-oxazoline 53 is the main productHowever, when the cyclopentanone is irradiated first and the irradiation is continued in the presence of azirine 35, the sole product is 3-oxazoline 54. Under the latter conditions, cyclopentanone reacts first by a Norrish type I cleavage and hydrogen transfer to yield 4-pentenal. This aldehyde reacts faster with the nitrile ylide than does the cyclic ketone still present, so that only 54 is formed. Norcamphor and camphor also react with azirine 35 under photolytic conditions via the Norrish type I reaction route to give 3-oxazolines 55 and 56. 

Whereas the cycloaddition of arylazirines with simple alkenes produces A -pyrrolines, a rearranged isomer can be formed when the alkene and the azirine moieties are suitably arranged in the same molecule. This type of intramolecular photocycloaddition was first detected using 2-vinyl-substituted azirines (75JA4682). Irradiation of azirine (54) in benzene afforded a 2,3-disubstituted pyrrole (55), while thermolysis gave a 2,5-disubstituted pyrrole (56). Photolysis of azirine (57) proceeded similarly and gave 1,2-diphenylimidazole (58) as the exclusive photoproduct. This stands in marked contrast to the thermal reaction of (57) which afforded 1,3-diphenylpyrazole (59) as the only product. 

When the chain between the azirine ring and the alkene end is extended to three carbon atoms, the normal mode of 1,3-intramolecular dipolar cycloaddition occurs. For example, irradiation of azirine (73) gives A -pyrroline (74) in quantitative yield 77JA1871). In this case the methylene chain is sufficiently long to allow the dipole and alkenic portions to approach each other in parallel planes. 

A variety of 1-azirines are available (40-90%) from the thermally induced extrusion (>100 °C) of triphenylphosphine oxide from oxazaphospholines (388) (or their acyclic betaine equivalents), which are accessible through 1,3-dipolar cycloaddition of nitrile oxides (389) to alkylidenephosphoranes (390) (66AG(E)1039). Frequently, the isomeric ketenimines (391) are isolated as by-products. The presence of electron withdrawing functionality in either or both of the addition components can influence the course of the reaction. For example, addition of benzonitrile oxide to the phosphorane ester (390 = C02Et) at... 

Diels-Alder cycloaddition of 2/f-azirines 23 with cyclopentadienones provides 3//-azepines 25 in excellent yields by electrocyclic ring opening, with concomitant loss of carbon monoxide, of the initially formed, nonisolable cycloadducts 24, followed by a [1,5]-H shift in the resulting 2//-azepines.31 108... 

Azcpincs under acid conditions reportedly117-225 yield aniline derivatives although ring contraction to pyridines is more usual. Thus, highly substituted 3//-azepines, e.g. 28, with a vacant 7-position, formed by cycloaddition of 2//-azirines with cyclopentadienones, on heating in acetic acid isomerize rapidly to the correspondingly substituted anilines 29.117... 

By analogy with the formation of3//-azepines by cycloaddition of 2//-azirines withcyclopenta-dienones, l,3-diphenyl-2//-inden-2-one (58) and its dibenzo analog 60 enter into [4 + 2] cycloadditions with 27/-azirines to give 3//-2-benzazepines 59 and phenanthro[9,10-e]azepincs 61, respectively.96... 

There has been some investigation of auxiliary-controlled cycloadditions of azir-ines. Thus, camphor-derived azirine esters undergo cycloaddition with dienes, with poor diastereoselectivity [70]. The same azirines were also observed to react unselectively with phenylmagnesium bromide. Better selectivities were obtained when Lewis acids were used in the corresponding cycloaddition reactions of 8-phe-nylmenthyl esters of azirine 2-carboxylates (Scheme 4.48) [71]. The same report also describes the use of asymmetric Lewis acids in similar cycloadditions, but mediocre ees were observed. 

Oxazole formation can be envisaged as proceeding by three possible pathways 1,3-dipolar cycloaddition of a free ketocarbene to the nitiile (Path A), the formation and subsequent 1,5-cyclisation of a nitrile ylide (Path B) or the formation and subsequent rearrangement of a 2-acyl-2//-azirine (Path C) (Scheme 9). 

The highly strained and reactive 2iT-azirines have been extensively studied for various synthetic purposes, such as ring expansion reactions, cycloaddition reactions, preparation of functionalized amines and substituted aziridines. The older literature on azirines in synthesis has extensively been reviewed [69]. Concerning azirines with defined chirality only scarce information is available. Practically all reactions of azirines take place at the activated imine bond. Reduction with sodium borohydride leads to cz5-substituted aziridines as is shown in Scheme 48 [26,28]. 

The first example of a [ 6 + 4] cycloaddition of a nitrile ylid has recently been reported104 irradiation of 3-phenyl-2,2-dimethyl-2i/-azirine (129) in the presence of 6,6-dimethylfulvene (130) in cyclohexane gave the [n6 + 4] adduct 131 together with the [ 4 + 2] adduct 132. 

Although highly reactive, 2/7-azirines are of considerable synthetic interest and serve as a source of the 3-fluoro-4//-l, 3-diazepines 86. Reaction of 80 with difluorocarbene in the presence of furfural gave 86, rather than the expected furfural-derived products 83. Rearrangement of the initial 1,3-dipolar intermediate 81 to 84 and then cycloaddition of 84 with 80 are proposed as key steps in the reaction the intermediate cycloadduct 85 gave 86 on base-induced elimination of HF. Nucleophilic displacement of the fluoro group in 86 provided access to further substituted 1,3-diazepines <06TL639>. 

The palladium-catalyzed trimethylenemethane reaction with tropanones was reported in 1987 by Trost and Seoane and is the first example of a [6 + 3]-cycloaddition.130 Chromium-mediated [6 + 3]-cycloadditions of two types have been described-one in which the chromium complex activates the six-carbon component and one in which the chromium complex activates the three-atom component. An example of the first type involves the reaction of a cycloheptatriene-Cr(CO)3 complex with azirines to give cyclic imines in moderate yields (Scheme 40).131... 

Photolytic cleavage of 2,3-disubstituted 2H-azirines or monoaryl-2H-azirines provides access to nitrile yiides with the structure 280.1,3-Dipolar cycloaddition of the in situ generated yiides to Cjq affords mono- or disubstituted pyrrolo fullerenes such as 281 (Scheme 4.50) [319, 320]. Aliphatic 2H-azirines are not reactive, as they have shorter excitation wavelengths than the phenylic substituted 2-azirines. 

Extensive work has been done to determine and understand the factors controlling diastereoselectivity in the cycloaddition of nitrile oxides to alkenes but very little is known about nitrile ylides in this regard. Work on their reactions with alkenes that are geminally disubstituted with electron-withdrawing groups (e.g., 187) has illustrated some of the difficulties in such studies. When the imidoyl chloride-base route was used to generate the nitrile ylides it was found that the products 188 epimerized under the reaction conditions. When the azirine route was used, the reaction was complicated by the photochemical isomerization of the dipolarophiles (96,97). Thus, in both cases, it proved impossible to determine the kinetic product ratio. 

The intermediacy of the nitrile ylide was demonstrated by a trapping experiment using methyl acrylate in which it was found that the formation of 312 was entirely suppressed. Interestingly and unexpectedly, the nitrile ylide 310 (R =Me, R =Ph) failed to follow a similar path and reacted only via cycloaddition of the nitrile ylide to the double bond of the precursor azirine 313 to give 314. Its failure to undergo 1,5-electrocyclization was attributed to steric destabilization of the required syn isomer. 

On irradiation, (Z)-2-styryl-2//-azirines, e.g. (249), undergo analogous ring fission, followed by intramolecular 1,7-dipolar cycloadditions of the resulting nitrile ylide to give 1 -phenyl-3//-2-benzazepines in high yield (80%) (75JA4682). Naphthoazepines have been prepared similarly. 

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